Clin Res Cardiol (2021)
DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Circulating Vascular Endothelial Growth Factor Beta is a Candidate Biomarker for Cardiovascular Risk Stratification in Association with Obesity and Diabetes
C. Schulte1, C. Müller1, J. E. Duque Escobar1, T. Tong1, K. J. Lackner2, A. Schulz2, S. Blankenberg3, V. Salomaa4, P. S. Wild5, T. Zeller1
1Allgemeine und Interventionelle Kardiologie, Universitäres Herz- und Gefäßzentrum Hamburg GmbH, Hamburg; 2Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Klinik für Kardiologie, Universitäres Herz- und Gefäßzentrum Hamburg GmbH, Hamburg; 4THL-National Institute for Health and Welfare, Helsinki, FI; 5Präventive Kardiologie und Medizinische Prävention, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;
Background: The blood-based transcriptome changes in association with body weight but no data on specific transcripts is available in a longitudinal study design. Monocytes play a crucial role in angiogenesis and the development of atherosclerosis is linked to cardiovascular risk factors such as diabetes and obesity. Monitoring monocytic genome-wide gene expression patterns could aid to identify biomarkers of the body’s adjustment to weight change and diabetes in the general population and improve cardiovascular risk stratification.


Objective: To apply transcriptome screening analysis to identify novel biomarker candidates associated with BMI and diabetes as cardiovascular risk factors and test association with clinical endpoints.


Methods: Transcriptome-wide monocytic gene expression changes were screened in relation to change in BMI over a time period of 5 years in a population-based Gutebnberg Health study, including data from 1,092 participants. Functional enrichment of BMI-related genes (FDR<0.01) was tested based on pathway databases and selected gene sets. Serum VEGFB levels were quantified in a subset of the 1,092 subjects and validated in serum from n=1,895 individuals from the FINRISK study. In-vitro, THP1 cells were stimulated with recombinant VEGFB.


Results: In the screening population, monocytic mRNA expression changes of 143 genes were significantly associated with change in BMI with top genes including VEGFB.  Decreased VEGFB mRNA levels strongly associated with increased BMI (p=2.8x10-9). VEGFB was top among 28% of BMI related genes enriched for a signature of more rapid biological aging associated with weight gain. Lower levels of monocytic VEGFB mRNA were associated with increased mortality (p=0.0035) following adjustment for age and sex (88 deaths among 1,527 individuals over 8 years) and incident diabetes (p=0.01) (54 diabetics among 1,122 individuals over 5 years). VEGFB serum protein in a subset of n=224 subjects was inversely correlated to monocytic VEGFB mRNA from the same participants (r=-0.2, p=0.0024). Serum VEGFB was validated to be elevated with increased BMI in n=1,511 non-cases. In-vitro, monocyte-like cell line THP-1 was stimilated with VEGFB recombinant protein, which resulted in a dose-dependent downregulation of VEGFB mRNA levels.


Conclusion: Decreased monocytic gene expression of VEGFB was related to increased body mass index, increased risk of diabetes and all-cause mortality. Serum VEGFB protein associates positively with BMI and diabetes, which seems to be explained by a negative feed-back mechanism. Serum-based circulating VEGFB is a potential novel biomarker candidate for weight-related diabetes risk and cardiovascular risk evaluation.
https://dgk.org/kongress_programme/jt2021/aP817.html